Are You Confident of the Diagnosis?

Characteristic findings on physical examination

Patients present with pigmented macules in and around the mouth, on the digits, and on the genitalia. Hyperpigmented macules are typically more prominent on the lips, around the mouth and eyes, and on the buccal mucosa but may be more subtle on the palms, soles, anal area, and fingers. Polyps in the small bowel may lead to abdominal pain, obstruction, or rectal bleeding. Some individuals have a positive family history. Umbilical pigmentation is rare but can be one of the earliest signs of Peutz-Jeghers syndrome (PJS).

Expected results of diagnostic studies

Genetic testing for mutations in serine/threonine protein kinase 11 (STK11) on chromosome 19p13.3 is clinically useful. About 3/4 of familial cases and 1/2 of sporadic cases will have abnormalities of STK11 detected by current genetic methods. Different genetic mutations likely account for the other cases, and there is variable penetrance of these abnormalities.

Diagnosis confirmation

Criteria for diagnosis as outlined in the Beggs et al article require one of the following to be present:

Two or more histologically confirmed PJ polyps

Any number of PJ polyps detected in an individual who has a family history of PJS in close relative(s)

Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in close relative(s)

Any number of PJ polyps in an individual who also has characteristic mucocutaneous pigmentation

Laugier-Hunziker syndrome (LHS) is associated with pigmentation of the nail unit and may be associated with pigmented macules on oral, genital, anal, conjunctival and esophageal mucosal surfaces. Volar macules are more common in Peutz-Jeghers syndrome, although they may occur in LHS. Most cases of LHS are non-familial, although rare familial cases have been reported. LHS is not associated with the genetic changes or internal associations noted with PJS.

Neurofibromatosis, LEOPARD syndrome, Carney Complex, racial patterned lentiginosis, and post inflammatory hyperpigmentation may all be associated with pigmented macules and should be considered in the clinical differential diagnosis when confronted with a patient that has multiple pigmented macules. The skin findings help establish the diagnosis because of the pattern and distribution of lesions. Pigmented skin lesions themselves are not associated with diagnostic histologic features but exhibit the histologic changes of ordinary lentigines or mucosal melanotic macules.

Who is at Risk for Developing this Disease?

Peutz-Jeghers syndrome is an autosomal dominant disorder with an equal sex incidence. About half of cases are thought to result from a spontaneous mutation. About 1 in 200,000 individuals is thought to be affected.

What is the Cause of the Disease?

Etiology

Peutz-Jeghers syndrome is caused by a mutation in a serine threonine phosphatase and tensin homologue kinase encoded in a gene on chromosome 19p13.3. The gene is known as STK11 (LKB1). Some mutations alter the interaction with phosphatase and tensin homolog (PTEN).

Patients with polycystic ovary syndrome and a genetic polymorphism in STK11 have developed Peutz-Jeghers like pigmentation of the mucosa, suggesting a relationship between the two disorders.

Pathophysiology

The pathogenesis is not fully understood at this time.

Systemic Implications and Complications

The presence of pigmented macules in and around the mouth, on the buccal mucosa, the digits, and the genitalia are usually the initial clue to the diagnosis. Macules may have a brown or bluish appearance. Macules may occur around the eyes, the nose, and the anus. Affected individuals in their teens and twenties may develop cramping abdominal pain. Some individuals may present with obstruction, intussusception, or rectal bleeding. Clubbing of the fingers may be noted, and some individuals may have a hormone secreting tumor that leads to precocious puberty.

The risk of cancer is markedly increased. Data from the St. Mark's polyposis registry suggests that about 1/3 of patients develop cancer by age 65. The following cancers are listed in order of decreasing relative risk: small intestine, stomach, pancreas, colon, esophagus, ovary, lung, uterus, breast, and cervix. Sex cord tumors and calcifying Sertoli cell tumors have been noted in affected individuals and some tumors secrete estrogen which may be associated with gynecomastia.

Treatment Options

Once the diagnosis is established, evaluation of other family members is essential. Endoscopic surveillance and laporoscopic removal of symptomatic polyps have become the standard method of follow-up. Capsule endoscopy is becoming a preferred method of follow-up and double balloon endoscopy seems to be a promising method of removing polyps.

Optimal Therapeutic Approach for this Disease

Once the diagnosis has been established and family members have been screened for the disease, affected individuals should be counseled to refrain from using tobacco products. Alcohol should only be used in moderation, and other healthy lifestyle changes should be instituted.

Recommendations vary, but careful screening is essential. Screening should begin at 40 years of age or 5-10 years before the youngest individual developed cancer. The cost effectiveness of surveillance is still under active study.

Patient Management

Recommendations for follow-up and surveillance of patients with Peutz-Jeghers syndrome vary. The following recommendations are from the thoughtful review by Beggs AD, Latchford AR, Vasen HFA, et al as published in 2010 and in our opinion represent the current best practices as supported by the scientific literature.

--Gastrointestinal tract: Upper GI endoscopy and colonoscopy as a baseline at age 8. If polyps are detected continue every 3 years until age 50. If no polyps are detected, repeat at age 18 and continue every 3 years after that until age 50. Video capsule endoscopy every 3 years from age 8. Colonoscopy every 1-2 years after age 50.

--Breast: Monthly breast self examination from age 18 on, annual breast MRI from age 25-50, and annual mammography after age 50. The overexpression of aromatase that leads to growth of breast tissue can be treated with aromatase inhibitors or gynecomastia can be treated with subcutaneous mastectomy in some cases.

--Genital: Annual physical and testicular examination until age 12, testicular ultrasound if abnormalities are detected. Cervical smear with liquid based chromatography every 4 months from age 25 on.

--Skin lesions: Laser or intense pulse light therapy can be used to treat problematic pigmented lesions.

Methods for screening of small intestinal polyps are changing. Wireless capsule endoscopy has been shown to better detect small intestinal polyps when compared to traditional radiographic methods. Magnetic resonance imaging (MRI) is more sensitive and exposes individuals to less radiation than computed tomography (CT) scans with oral contrast. Combinations of some of these methods may be helpful because capsule endoscopy helps identify small polyps efficiently whereas MRI is better able to determine polyp size.

Polyps in the mid-small bowel have traditionally been removed by primary surgical resection and intraoperative enteroscopy (IOE). The newer technique of double balloon endoscopy (DBE) is a less invasive but longer procedure with a quicker recovery time. In experienced hands, this technique works well and IOE can be held in reserve should complications or other difficulties arise.

Pancreatic cancer surveillance may include endoscopic retrograde cholangiopancreatography (ERCP) and endoluminal ultrasonography (EUS). The optimal screening protocols to detect pancreatic cancer are under study. Optimal ovarian and uterine surveillance is also under investigation.

Modulating the mTOR pathway appears to be a promising area of research, but clinical trials are not complete. Because medications such as sirolimus and everolimus have significant side effects, further research is needed. Celecoxib affects the COX2 pathway and may become a useful treatment as well, but further study of this treatment is warranted.

Unusual Clinical Scenarios to Consider in Patient Management

K-Ras and p16 mutation status may help stratify the risk of affected individuals. Identifying other family members that may be at risk of disease is a critical component to management.